title: In-vitro selection of HIV-1 variants resistant to non-nucleoside reverse transcriptase inhibitors in monocyte-derived macrophages.
abstract: Unlike the selection of HIV-1 variants resistant to anti-retroviral drugs in human peripheral blood mononuclear cells and T cell lines, induction of resistance in monocyte-derived macrophages has not been widely studied. Since macrophages serve as a potential HIV-1 reservoir in humans, knowledge of the effect of anti-retroviral drugs on macrophage-tropic HIV-1 isolates may help in the design of a strategy for prolonged suppression of viral replication. In-vitro selection and drug susceptibility testing of macrophage-tropic HIV-1 variants with reduced sensitivity to two non-nucleoside reverse transcriptase inhibitors, atevirdine and delavirdine (both bis-heteroarylpiperazines), is described here. The atevirdine-resistant isolate was cross-resistant to delavirdine, and the delavirdine-resistant isolate was cross-resistant to atevirdine. Interestingly, the atevirdine-resistant isolate, but not the delavirdine-resistant isolate, was also cross-resistant to nevirapin while the inhibition of viral replication of both isolates in macrophages by zidovudine was the same as that in the parental HIV-1 strain. Nucleotide sequence analysis of the resistant macrophage-tropic HIV-1 isolates showed that the atevirdine-induced resistance was due to a single amino acid change at codon 106 and that the delavirdine-induced resistance could be attributed to an amino acid change at codon 236. This study demonstrates that monocyte-derived macrophages can be used to investigate the phenotypic and genotypic acquisition of anti-retroviral drug resistance of macrophage-tropic HIV-1.
authors.affiliation: Eijkman-Winkler Institute of Medical Microbiology, University of Utrecht, University Hospital, The Netherlands.
authors.forename: A M
authors.initials: AM
authors.lastname: Been-Tiktak
authors.forename: C J
authors.initials: CJ
authors.lastname: de Haas
authors.forename: L
authors.initials: L
authors.lastname: de Graaf
authors.forename: C A
authors.initials: CA
authors.lastname: Boucher
authors.forename: J
authors.initials: J
authors.lastname: Verhoef
authors.forename: J C
authors.initials: JC
authors.lastname: Borleffs
authors.forename: H S
authors.initials: HS
authors.lastname: Nottet
authors.forename: R
authors.initials: R
authors.lastname: Schuurman
mesh_terms: D000595:Amino Acid Sequence; D020008:Delavirdine / Q000494:pharmacology; D004352:Drug Resistance, Microbial / Q000235:genetics*; D054303:HIV Reverse Transcriptase / Q000737:chemistry / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008264:Macrophages / Q000821:virology*; D008969:Molecular Sequence Data; D009000:Monocytes; D010879:Piperazines / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D017386:Sequence Homology, Amino Acid; D015215:Zidovudine / Q000494:pharmacology
chemical_list: D010879:Piperazines; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D020008:Delavirdine; D054303:HIV Reverse Transcriptase; C076632:atevirdine